Limits...
Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements

View Article: PubMed Central - PubMed

ABSTRACT

2-Hydroxypropyl-Beta-Cyclodextrin (HPβCD) can be used to treat Niemann-Pick type C disease, Alzheimer’s disease, and atherosclerosis. But, a consequence is that HPβCD can cause hearing loss. HPβCD was recently found to be toxic to outer hair cells (OHCs) in the organ of Corti. Previous studies on the chronic effects of in vivo HPβCD toxicity did not know the intra-cochlear concentration of HPβCD and attributed variable effects on OHCs to indirect drug delivery to the cochlea. We studied the acute effects of known HPβCD concentrations administered directly into intact guinea pig cochleae. Our novel approach injected solutions through pipette sealed into scala tympani in the cochlear apex. Solutions were driven along the length of the cochlear spiral toward the cochlear aqueduct in the base. This method ensured that therapeutic levels were achieved throughout the cochlea, including those regions tuned to mid to low frequencies and code speech vowels and background noise. A wide variety of measurements were made. Results were compared to measurements from ears treated with the HPβCD analog methyl-β-cyclodextrin (MβCD), salicylate that is well known to attenuate the gain of the cochlear amplifier, and injection of artificial perilymph alone (controls). Histological data showed that OHCs appeared normal after treatment with a low dose of HPβCD, and physiological data was consistent with attenuation of cochlear amplifier gain and disruption of non-linearity associated with transferring acoustic sound into neural excitation, an origin of distortion products that are commonly used to objectively assess hearing and hearing loss. A high dose of HPβCD caused sporadic OHC losses and markedly affected all physiologic measurements. MβCD caused virulent destruction of OHCs and physiologic responses. Toxicity of HPβCD to OHC along the cochlear length is variable even when a known intra-cochlear concentration is administered, at least for the duration of our acute studies.

No MeSH data available.


Related in: MedlinePlus

Distortion product otoacoustic emission (DPOAE) amplitudes at 2f1- f2 evoked from f2 ≈ 6 kHz, f2 / f1 = 1.2 kHz, L2 = 50 dB, L1 = 10 dB re. L2.The blue rectangle identifies the 15 minute injection. Values to the left of the rectangle are average DPOAE amplitudes from ~10 minutes of pre-injection data. The microphone noise floor was approximately -20 dB SPL. Measurement rankings on the y-axis were determined by the effect of the ototoxic solution: measurements associated with the smallest effect are at the top of the figure, progressing to the largest effect at the bottom of the figure. MβCD totally abolished DPOAEs, while the remaining ototoxic solutions caused transient declines in amplitudes that did not return to pre-injection levels. N = 3 for each treatment.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5383289&req=5

pone.0175236.g005: Distortion product otoacoustic emission (DPOAE) amplitudes at 2f1- f2 evoked from f2 ≈ 6 kHz, f2 / f1 = 1.2 kHz, L2 = 50 dB, L1 = 10 dB re. L2.The blue rectangle identifies the 15 minute injection. Values to the left of the rectangle are average DPOAE amplitudes from ~10 minutes of pre-injection data. The microphone noise floor was approximately -20 dB SPL. Measurement rankings on the y-axis were determined by the effect of the ototoxic solution: measurements associated with the smallest effect are at the top of the figure, progressing to the largest effect at the bottom of the figure. MβCD totally abolished DPOAEs, while the remaining ototoxic solutions caused transient declines in amplitudes that did not return to pre-injection levels. N = 3 for each treatment.

Mentions: Cubic DPOAE amplitudes were measured at 2f1- f2 with an arbitrarily chosen f2 ≈ 6 kHz (Fig 5). Individual-ear DPOAE amplitude fine structure was considered by choosing the f2 primary-tone frequencies closest to 6 kHz that produced a peak in the 2f1- f2 DPOAE amplitude. Injection of artificial perilymph did not affect DPOAE amplitudes in control ears. With 13 mM HPβCD treatment, DPOAE amplitudes dramatically declined during the injection but gradually recovered toward near pre-injection levels. With salicylate and 27 mM HPβCD treatments, effects on DPOAE amplitude were longer, and did not fully recover. MβCD was the only treatment that totally abolished DPOAE amplitudes.


Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements
Distortion product otoacoustic emission (DPOAE) amplitudes at 2f1- f2 evoked from f2 ≈ 6 kHz, f2 / f1 = 1.2 kHz, L2 = 50 dB, L1 = 10 dB re. L2.The blue rectangle identifies the 15 minute injection. Values to the left of the rectangle are average DPOAE amplitudes from ~10 minutes of pre-injection data. The microphone noise floor was approximately -20 dB SPL. Measurement rankings on the y-axis were determined by the effect of the ototoxic solution: measurements associated with the smallest effect are at the top of the figure, progressing to the largest effect at the bottom of the figure. MβCD totally abolished DPOAEs, while the remaining ototoxic solutions caused transient declines in amplitudes that did not return to pre-injection levels. N = 3 for each treatment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383289&req=5

pone.0175236.g005: Distortion product otoacoustic emission (DPOAE) amplitudes at 2f1- f2 evoked from f2 ≈ 6 kHz, f2 / f1 = 1.2 kHz, L2 = 50 dB, L1 = 10 dB re. L2.The blue rectangle identifies the 15 minute injection. Values to the left of the rectangle are average DPOAE amplitudes from ~10 minutes of pre-injection data. The microphone noise floor was approximately -20 dB SPL. Measurement rankings on the y-axis were determined by the effect of the ototoxic solution: measurements associated with the smallest effect are at the top of the figure, progressing to the largest effect at the bottom of the figure. MβCD totally abolished DPOAEs, while the remaining ototoxic solutions caused transient declines in amplitudes that did not return to pre-injection levels. N = 3 for each treatment.
Mentions: Cubic DPOAE amplitudes were measured at 2f1- f2 with an arbitrarily chosen f2 ≈ 6 kHz (Fig 5). Individual-ear DPOAE amplitude fine structure was considered by choosing the f2 primary-tone frequencies closest to 6 kHz that produced a peak in the 2f1- f2 DPOAE amplitude. Injection of artificial perilymph did not affect DPOAE amplitudes in control ears. With 13 mM HPβCD treatment, DPOAE amplitudes dramatically declined during the injection but gradually recovered toward near pre-injection levels. With salicylate and 27 mM HPβCD treatments, effects on DPOAE amplitude were longer, and did not fully recover. MβCD was the only treatment that totally abolished DPOAE amplitudes.

View Article: PubMed Central - PubMed

ABSTRACT

2-Hydroxypropyl-Beta-Cyclodextrin (HPβCD) can be used to treat Niemann-Pick type C disease, Alzheimer’s disease, and atherosclerosis. But, a consequence is that HPβCD can cause hearing loss. HPβCD was recently found to be toxic to outer hair cells (OHCs) in the organ of Corti. Previous studies on the chronic effects of in vivo HPβCD toxicity did not know the intra-cochlear concentration of HPβCD and attributed variable effects on OHCs to indirect drug delivery to the cochlea. We studied the acute effects of known HPβCD concentrations administered directly into intact guinea pig cochleae. Our novel approach injected solutions through pipette sealed into scala tympani in the cochlear apex. Solutions were driven along the length of the cochlear spiral toward the cochlear aqueduct in the base. This method ensured that therapeutic levels were achieved throughout the cochlea, including those regions tuned to mid to low frequencies and code speech vowels and background noise. A wide variety of measurements were made. Results were compared to measurements from ears treated with the HPβCD analog methyl-β-cyclodextrin (MβCD), salicylate that is well known to attenuate the gain of the cochlear amplifier, and injection of artificial perilymph alone (controls). Histological data showed that OHCs appeared normal after treatment with a low dose of HPβCD, and physiological data was consistent with attenuation of cochlear amplifier gain and disruption of non-linearity associated with transferring acoustic sound into neural excitation, an origin of distortion products that are commonly used to objectively assess hearing and hearing loss. A high dose of HPβCD caused sporadic OHC losses and markedly affected all physiologic measurements. MβCD caused virulent destruction of OHCs and physiologic responses. Toxicity of HPβCD to OHC along the cochlear length is variable even when a known intra-cochlear concentration is administered, at least for the duration of our acute studies.

No MeSH data available.


Related in: MedlinePlus